Mast cells (MCs) are well known in allergic responses. Yet recent studies demonstrated their essential roles in inflammatory cardiometabolic diseases. By releasing inflammatory cytokines, chemokines, and proteases after degranulation, MCs activate vascular and inflammatory cells in the vasculature and endocrine organs. Pharmacological stabilization of MCs mitigates cardiometabolic diseases in mice. Alzheimer's disease (AD), a neurodegenerative chronic inflammatory disease, is the most common cause of dementia and disability in the elderly. It is the sixth leading cause of death in the U.S., affecting more than 5 million Americans alone, according to the Alzheimer's Association. A definitive diagnosis of AD is based on the presence of intraneuronal accumulation of the hyperphosphorylated microtubule-associated protein tau, known as neurofibrillary tangles (NFTs), and the extracellular deposition of neurotoxic ?-amyloid (A?) into senile plaques. Like in other inflammatory diseases, human AD brains have elevated protease expression, neuronal death and synapse loss, blood-brain barrier (BBB) leakage, and activation of inflammatory cells such as microglia and astrocytes. MCs are also present in human AD brains, mainly in the hippocampus, cerebral cortex, and thalamus, but studies have yet to test whether these cells participate directly in the pathogenesis or serve merely as another inflammatory hallmark. Our preliminary data demonstrated that plasma levels of MC tryptase and the MC activator IgE were elevated in patients with early stage AD. Using MC-deficient KitW-sh/W-sh mice crossbred with the APPSWE-PS1?e9+/? (APP-PS1) mice that develop cerebral amyloidosis, we demonstrated that the absence of MCs reduced A? deposition and senile plaque formation in the hippocampus and cerebral cortex, and reduced the numbers of total Iba-1-positive microglia and CD68-positive activated microglia in these regions. Brain tissue extract ELISA showed that the absence of MCs significantly reduced pathological A? species (A?1-40 and A?1-42). Adoptive transfer of in vitro-prepared MCs into KitW-sh/W-shAPP-PS1- recipient mice restored cortical and hippocampal A? deposition, microglia infiltration and activation, and tissue extract A?1-40 and A?1-42 contents. A preliminary water T-maze behavior test suggested that MC depletion and possibly pharmaceutical inhibition improve cognitive decline in APP-PS1 mice. Therefore, we hypothesize that MCs participate in AD by releasing inflammatory cytokines and proteases to promote microglia and T-cell activation, A? deposition and senile plaque formation, tau hyperphosphorylation and NFT formation, neuron synapse loss, and cerebrovascular cell activation and BBB leakage. We propose three aims: to examine whether mast cell depletion or inhibition protects mice from Alzheimer's disease; to examine whether genetic deficiency of IgE receptor Fc?R1 or anti-IgE antibody therapy protects mice from Alzheimer's disease, and; to investigate the molecular and cellular mechanisms by which mast cells contribute to Alzheimer's disease.